Gelling agent for polyethylene glycol

ABSTRACT

The present invention relates to gelling liquid polyethylene glycol at room temperature with calcium acetate.

FIELD OF THE INVENTION

The present invention relates to gelling liquid polyethylene glycol atroom temperature to produce a substantially translucent gel suitable foruse in pharmaceutical or cosmetic products.

BACKGROUND OF THE INVENTION

In recent years soft gelatin or soft elastic gelatin capsules havebecome a popular dosage form for the oral delivery of therapeuticagents, especially over-the-counter pharmaceuticals. These capsules aretypically filled with a liquid containing the active ingredient. Becauseof their soft, elastic character, some patients view these capsules aseasier to swallow than conventional tablets or hard gelatin capsules.Since the dosage form is generally swallowed, it is not necessary toflavor or otherwise mask the often unpleasant taste of thepharmaceutical. Soft gelatin capsules are also preferred to bulk liquidsbecause they are easier to transport and they avoid the need for thepatient to measure a prescribed amount of the liquid before dosing.

The fill material used in a soft gelatin capsules generally contains apharmaceutical dissolved or dispersed in a carrier that is compatiblewith the capsule wall. In addition to liquids, U.S. Pat. No. 4,935,243to L. Borkan et al. suggests that the fill material may take the form ofa semi-solid, solid, or gel. Conventional tablets or pellets containingan active ingredient are examples of solid fill materials that may beencapsulated within a soft gelatin capsule.

Semi-solid (dispersion) fill material are discussed in U.S. Pat. No.4,486,412 to D. Shah et al. A fill material containing anorally-administered antacid salt that is dispersed in a water-free,liquid carrier containing a major proportion of one or more polyalkyleneglycols and a minor proportion of a C₂ -C₅ polyol, such as propyleneglycol or glycerin. The carrier forms a stable dispersion of the antacidsalt and coats the antacid particles, thereby rendering themnon-reactive with the soft gelatin capsule wall.

U.S. Pat. No. 4,708,834 to Cohen et al. suggests a controlled releasepharmaceutical dosage form comprising a soft gelatin capsule thatencloses a water-soluble or dispersible gelled polymer matrix. The fillmaterial comprises an aqueous solution or dispersion of a polysaccharidegum, the pharmaceutical active and, optionally, an alcohol. The liquidfill is introduced into a soft gelatin capsule that contains a cationicgelling agent, which gels the liquid fill after it has been incorporatedinto the capsule shell. The alcohol used in the fill includes liquidpolyethylene glycols, lower alkanols, C₂ -C₄ polyols and mixturesthereof.

U.S. Pat. No. 5,071,643 to M. Yu et al. also discusses the use ofpolyethylene glycols (PEG) as a fill material in soft gelatin dosageforms. PEGs having an average molecular weight between 400-600 arepreferred for liquid fills, between 800-10,000 for semi-solid fills andbetween 10,000-100,000 for solid fills.

PCT Publication No. WO 91/07950 describes a soft or two-piece hardgelatin capsule shell containing benzodiazepine dissolved or suspendedin a gel. The gel contains by weight at least 63% of polyethylene glycol600, at least 4% of polyethylene glycol 4000 or 6000, and at least 21%of polyethylene glycol 600-4000. This gel fill cannot be expelled with asyringe at ambient temperature and therefore avoids the reported abuseof liquid filled capsules by intravenous drug abusers.

Remington's Pharmaceutical Sciences, 18th ed, Chapter 83, pp. 1539-40(1990), reports that gelling agents used to make gels for pharmaceuticaland cosmetic products, include sodium alginate and triethanolamine.

A need exists for a technique for gelling liquid polyethylene glycols atroom temperature to produce a substantially translucent gel, suitablefor use in the production of cosmetics or pharmaceutical dosage forms.

SUMMARY OF THE INVENTION

The present invention provides a technique for gelling liquidpolyethylene glycols at room temperature. The gel is suitable for use asa fill material in a soft gelatin capsule pharmaceutical dosage form, acarrier for a pharmaceutical in a topical formulation, or as a base fora cosmetic or dental care product.

The gel comprises a liquid polyethylene glycol, water and an effectiveamount of calcium acetate to gel the glycol. A effective amount of anactive ingredient, such as a deodorant or a pharmaceutical, is dissolvedor suspended in the gel.

The gel of the present invention has a substantially translucentappearance, and when used to fill a soft gelatin capsule or as base in acosmetic care product, the resulting product has an elegant,substantially translucent appearance.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides a technique for gelling liquidpolyethylene glycols at room temperature. The resulting gel issubstantially translucent and may be used as a carrier for apharmaceutical in a soft gelatin capsule, topical formulation ortwo-piece hard gelatin capsule.

Since calcium acetate spontaneously gels liquid polyethylene glycol atroom temperature, the present invention provides a number of processingadvantages. No heating or cooling is required, so the manufactureprocess is simple and inexpensive. The resulting gel also has relativelyfew components, which helps to reduce the number of mixing steps in theprocess.

The liquid polyethylene glycol has an average molecular weight of about600 or less, preferably about 200 to about 600, and most preferablyabout 300 to about 400. A minor proportion of water is also used inconjunction with the polyethylene glycol. The gel generally comprises byweight about 40 to about 80, preferably about 50 to about 70, percentpolyethylene glycol and about 1 to about 40, preferably about 5 to about25, percent water. Unless otherwise stated, the percentages recitedherein are by weight of the total weight of the gel fill material, i.e.,both the gel and active ingredient.

The calcium acetate is employed in an amount effective to form a gel atroom temperature that has the desired viscosity or gel strength.Generally the gel contains by weight from about 0.5 to about 10,preferably about 0.5 to about 5 percent calcium acetate. The calciumacetate may me used in either an anhydrous or hydrated form.

The viscosity or gel strength is dependent upon the end use of the gel.For pharmaceutical applications, such as for use as the fill material ina soft gelatin capsule, the gel should be sufficiently viscous so thatit cannot be expelled at room temperature with a syringe. This featurehelps to protect against possible intravenous abuse of the drug as wellas product tampering. For topical pharmaceutical and/or cosmeticapplications, such as for use as a spreadable gel, ointment or lotion,the gel need not be as viscous.

The viscosity or gel strength is also affected by an increase ordecrease in the amount of shear applied in the manufacturing process. Itwas found that the amount of shear and the length of mixing have aneffect on the strength of the gel. A large amount of shear decreases thestrength of the gel and, likewise, a minimal amount of shear increasesthe strength of the gel. Also, it was found that the best way tomaximize the strength of the gel is by decreasing shear and, mostpreferably, by eliminating any mixing. Therefore, a dual head fillingprocess directly into the soft gelatin capsule without any mixing is thebest means for achieving a strong gel fill material suitable for softgelatin capsule applications. A manufacturing process with sufficientmixing is the best means for achieving a low viscosity gel materialsuitable for topical applications.

Solubilizing agents may also be employed to enhance the solubility ordispersibility of the active ingredient in the gel. Suitable agentsinclude:

    ______________________________________                                        % (wt.)      Component                                                        ______________________________________                                        0-15         Propylene Glycol                                                 0-15         Glycerin                                                         0-10         Ethanol                                                          0-20         Sodium Acetate (anhydrous, hydrate)                              ______________________________________                                    

The pharmaceutical active used in the present invention can be anymedication which can be administered orally to transmit the active agentinto the gastrointestinal tract and into the bloodstream attherapeutically effective levels.

The pharmaceutical active(s) is present in the dosage form in atherapeutically effective amount, which is an amount that produces thedesired therapeutic response upon oral administration, and can bereadily determined by one skilled in the art. In determining suchamounts, the particular compound being administered, thebio-availability characteristics of the compound, the dose regiment, theage and weight of the patient, and other factors must be considered.Pharmaceuticals suitable for use in the invention include acetaminophen,famotidine, chlorpheniramine, pseudoephedrine, dextromethorphan,diphenhydramine, brompheniramine, phenylpropanolamine, clemastine,terfenadine, astemizole, loratadine, pharmaceutically acceptable saltsthereof and mixtures thereof.

Various other pharmaceutically acceptable excipients may be included inthe pharmaceutical dosage form, such as preservatives, e.g., methyl- orpropylparaben, and coloring agents.

In a preferred embodiment, a fill for a soft gelatin capsule containingabout 250 mg/ml of acetaminophen, comprises by weight from about 23 toabout 27 percent acetaminophen, from about 60 to about 70 percent PEG400, from about 10 to about 20 percent water, and from about 1 to about3 percent calcium acetate.

Suitable active ingredients for use in topical pharmaceuticalformulations include antifungals, anti-inflammatory corticosteroids,antibiotics, otic-active ingredients, ophthalmic-active ingredients,anti-acne medicaments, and nasal-active ingredients.

Suitable active ingredients for use in cosmetic and dental care productsinclude deodorants, sodium fluoride, anti-perspirants, perfumes, andskin moisturizers.

The amount of the active ingredient, whether a pharmaceutical or anactive in a cosmetic, employed in the gel will vary depending on thepotency of the active and the desired strength of the dosage form orproduct. Generally, the active ingredient comprises about 0.1 to about40, preferably about 0.2 to about 30, percent by weight of the total gelcomposition.

In a preferred embodiment of the present invention, the activeingredient, at the desired dosage, must also be sufficiently soluble ordispersible in the gel so that the resulting composition has a turbidityof less than about 1300 NTU (Nephelometric Turbidity Unit).

The gel is prepared by first forming an aqueous calcium acetatesolution. The active ingredient(s) is then mixed with the liquidpolyethylene glycol and the solubizing agent, if any, being used in theformulation. The aqueous calcium acetate solution is combined with theactives mixture at room temperature. It can be mixed gently for lowerviscosity gels (spreadable). For higher viscosity gels (semi-solidlike), the calcium acetate solution and the actives mixture are combinedin a dual head filling mechanism without any additional mixing. Themixture resulting from the dual head filling device is then leftundisturbed for about 5 to about 60 minutes to effect gelling.

The fill material of the present invention may be used in commerciallyavailable soft gelatin capsules, such as those commercially availablefrom R. P. Scherer or Banner Pharmacaps. Various sizes, shapes, andcolors can be used to accommodate different levels of activeingredients. The walls of the capsules have a substantially translucentor clear appearance. When the fill material of the present invention isintroduced into the capsule and gelled, the resulting dosage form has anelegant, translucent or clear appearance.

If a soft gelatin capsule dosage form is being prepared, the gel isformed at ambient room temperature in the capsule after the twocomponent mixture, namely the PEG/actives mixture and the calciumacetate solution, are injected separately. The needle on the syringe isused to puncture one end of the soft gelatin capsule so that theappropriate amount of the two component mixtures may be injected byhand. The capsule with fill material is allowed to set undisturbed atambient room temperature to effect gelling.

The fill material may also be introduced into the soft gelatin capsuleusing encapsulation equipment known in the art, such as that describedin U.S. Pat. No. 4,028,024 to Moreland, which is hereby incorporated byreference. Such equipment, however, requires the use of a dual head tointroduce the two component mixtures into the gelatin shell as separatestreams.

Further details of the use of gel as a fill material in a soft gelatincapsule may be found in copending, commonly assigned patent applicationSer. No. 08/366,945, filed on even date herewith, entitled "Soft GelatinPharmaceutical Dosage Form," which is hereby incorporated by reference.

Specific embodiments of the present invention are illustrated by way ofthe following examples. This invention is not confined to the specificlimitations set forth in these examples, but rather to the scope of theappended claims. Unless otherwise stated, the percentages, parts andratios given below are by weight.

The turbidity of the fill materials described in the following exampleswas measured using a Hach Ratio/XR Turbidimeter. The United StatesPharmacopedia defines turbidance as the light-scattering effect ofsuspended particles and turbidity as the measure of the decrease in theincident beam intensity per unit length of a given suspension. Thisinstrument measures turbidity within a range of 0.00 to 2000 NTU. As apoint of reference, the turbidity of water is zero. Samples of the fillmaterials, approximately 8 mL, were transferred to Fisher Brand 13×100mm culture tubes immediately after manufacture. The fill materialsamples were stored at ambient room temperature since they were madeseveral days in advance. The outer surface of each of the sample culturetubes was treated with silicone oil just prior to measuring theturbidity. The turbidity of the samples was measured at ambient roomtemperature. The turbidity of two sample tubes of each fill material wasmeasured and the average of the results is reported.

EXAMPLE 1

This Example reports the results of an experiment wherein differentsalts were evaluated as potential gelling agents for liquid polyethyleneglycol at room temperature.

For each of the tested salts, the composition shown below was preparedat room temperature by solubilizing the salt in water and then mixingwith PEG 400 to see if a gel would form at ambient room temperature.

    ______________________________________                                        Component     Amount (% w/w)                                                  ______________________________________                                        PEG 400       61.54                                                           Salt          7.69                                                            Water         30.77                                                           ______________________________________                                    

The following summarizes the results of the experiment:

    ______________________________________                                        Salt              Cation     Result                                           ______________________________________                                        Calcium Acetate   Ca.sup.2+  G                                                Sodium Acetate    Na.sup.1+  NG                                               Potassium Acetate K.sup.1+   NG                                               Zinc Acetate      Zn.sup.2+  NG                                               Ammonium Acetate  NH.sub.4.sup.1+                                                                          NG                                               Magnesium Acetate Mg.sup.2+  NG                                               Barium Acetate    Ba.sup.2+  NG                                               Calcium Propionate                                                                              Ca.sup.2+  NG                                               ______________________________________                                         G = gel formed                                                                NG = no gel formation                                                         Note: Zinc acetate is relatively insoluble in water and the resulting         solution was supersaturated.                                             

The above unexpectedly demonstrates that calcium acetate gels liquidpolyethylene glycol whereas the other tested salts do not have thiseffect.

EXAMPLE 2

This Example discloses a composition of the present invention which wasgelled at room temperature with calcium acetate. The gel contained:

    ______________________________________                                        Component      Amount (% w/w)                                                 ______________________________________                                        Calcium Acetate                                                                              5.0                                                            Water          17.0                                                           PEG 400        75.0                                                           Glycerin       3.0                                                            ______________________________________                                    

The sample was prepared as follows:

1) Add calcium acetate to water and mix until the calcium acetate isdissolved.

2) Add PEG 400 and mix.

3) Add glycerin and mix.

4) Gel forms at room temperature after about 2 minutes.

The resulting gel had a translucent appearance.

EXAMPLE 3

This Example discloses a acetaminophen-containing composition of thepresent invention which was gelled at room temperature with calciumacetate. The gel contained:

    ______________________________________                                        Component      Amount (% w/w)                                                 ______________________________________                                        Calcium Acetate                                                                              1.5                                                            Water          6.0                                                            PEG 400        61.2                                                           Ethanol        6.8                                                            Acetaminophen  24.5                                                           ______________________________________                                    

The sample was prepared as follows:

1) An aqueous solution containing 20% (wt.) of calcium acetate wasprepared.

2) The following ingredients were mixed to form an actives mixtures:

    ______________________________________                                        Component      Amount (% w/w)                                                 ______________________________________                                        Acetaminophen  26.5                                                           PEG 400        66.2                                                           Ethanol        7.3                                                            ______________________________________                                    

3) One part of the solution of step 1) was mixed with nine parts of themixture of step 2). The resulting mixture was allowed to gel at roomtemperature.

The resulting gel had a translucent appearance.

EXAMPLE 4

This Example discloses a composition of the present invention which wasgelled at room temperature with calcium acetate. The gel contained:

    ______________________________________                                        Component      Amount (% w/w)                                                 ______________________________________                                        PEG 400        80.36                                                          Calcium Acetate                                                                              1.78                                                           Water          17.86                                                          ______________________________________                                    

The gel was prepared as follows:

1) Weigh calcium acetate and water. Sonicate/mix to dissolve calciumacetate.

2) In a separate beaker, weigh PEG 400 and stir.

3) Add calcium acetate solution to PEG 400 while mixing. Continue to mixuntil system gels.

4) Sonicate gel to remove air.

The fill material was substantially clear and had a turbidity of 195NTU, although some air was noted in the tested samples.

EXAMPLE 5

This Example discloses a fill material of the present inventioncontaining 200 mg/mL of acetaminophen which was gelled at roomtemperature with calcium acetate. The fill material contained:

    ______________________________________                                        Component      Amount (% w/w)                                                 ______________________________________                                        Acetaminophen  18.24                                                          PEG 400        65.70                                                          Calcium Acetate                                                                              1.46                                                           Purified Water 14.60                                                          ______________________________________                                    

The samples was prepared as follows:

1) Weigh calcium acetate and water. Sonicate/mix to dissolve calciumacetate.

2) In a separate beaker, weigh active and PEG 400. Mix to formactive/PEG slurry.

3) Add calcium acetate solution to PEG while mixing. Continue to mixuntil system gels.

4) Sonicate gel to remove air.

The fill material was substantially translucent and had a turbidity of865 NTU, although some air was noted in the tested samples.

The resulting fill material could be expelled at room temperature with asyringe having an 18 gauge needle because the strength of the gel wasweakened by the mixing step. It was found that the gel strength can bemaximized by eliminating the mixing step. The sample was prepared asecond time by first hand-filling a soft gelatin capsule shell with theactive/PEG slurry with a syringe. Then the calcium acetate solution wasinjected into the capsule shell containing the active/PEG slurry. Theresulting mixture was allowed to gel at room temperature in the capsuleshell. The capsule was then cut open with a scalpel and the fillmaterial was observed to be a solid material.

Various modifications can be made to the above-described embodimentswithout departing from the spirit and scope of the present invention.

What is claimed is:
 1. A gel composition, comprising:about 40 to about80 percent polyethylene glycol having an average molecular weight ofabout 600 or less; about 1 to about 40 percent water; and about 0.5 toabout 10 percent calcium acetate, by weight of the gel.
 2. Thecomposition of claim 1 wherein said polyethylene glycol has an averagemolecular weight of about 200 to about
 600. 3. The composition of claim1 comprising:about 50 to about 70 percent polyethylene glycol; about 5to about 25 percent water; and about 0.5 to about 5 percent calciumacetate, by weight of the gel.
 4. The composition of claim 3 whereinpolyethylene glycol has an average molecular weight of about 300 toabout
 400. 5. A cosmetic comprising the gel of claim
 1. 6. A dental careproduct comprising the gel of claim
 1. 7. A method of gelling liquidpolyethylene glycol, comprising combining a liquid polyethylene glycolhaving an average molecular weight of about 600 or less with water and agelling effective amount of calcium acetate, wherein the resulting gelcomprises about 40 to about 80 percent polyethylene glycol, about 1 toabout 40 percent water, and about 0.5 to about 10 percent calciumacetate, by weight of the gel.
 8. The method of claim 7 wherein saidcombining a liquid polyethylene glycol having an average molecularweight of about 600 or less with a gelling effective amount of calciumacetate is carried out a room temperature.
 9. The method of claim 8wherein said calcium acetate is in the form of an aqueous solution whenit is combined with the polyethylene glycol.
 10. The method of claim 7wherein said gel has a turbidity less than about 1300 NTU.
 11. Themethod of claim 7 wherein said gel comprises:about 50 to about 70percent polyethylene glycol; about 5 to about 25 percent water; andabout 0.5 to about 5 percent calcium acetate, by weight of the gel. 12.The method of claim 7 wherein said polyethylene glycol has an averagemolecular weight of about 300 to about
 400. 13. The composition of claim1 having a turbidity less than about 1300 NTU.
 14. The composition ofclaim 1 wherein said gel is substantially translucent.
 15. The method ofclaim 7 wherein the gelled polyethylene glycol is substantiallytranslucent.
 16. The method of claim 9 wherein said polyethylene glycolis combined with said aqueous solution of calcium acetate without anyadditional mixing.